The proposed studies focus primarily on the use of axonal transport techniques to investigate pathogenetic mechanisms of disease. The strategy is based on a correlation of ultrastructural pathology and axonal transport studies of identified proteins. This strategy has been employed in my ongoing studies of the axonal transport of neurofilament proteins in models of neurofilamentous pathology. The prototype for these studies is B,B'-imino-dipropionitrile (IDPN) intoxication in the rat. Our studies to date have shown that: 1) IDPN dramatically impairs slow axonal transport, particularly affecting movement of neurofilament triplet proteins. 2) Fast axonal transport and retrograde transport have been normal in studies to date. 3) The defect in neurofilament transport can be detected one day after administration of IDPN and thus precedes structural changes in the axon. 4) The major pathologic consequences of the transport defect are the accumulation of neurofilaments in the very proximal axon and, distal to this region, slowly progressive atrophy of the axon. Further studies on the role of axonal transport in the pathogenesis of the lesion and on the pathology of IDPN intoxication and its relationship to motor neuron diseases are planned.